Systemic lupus erythematosus (SLE) is considered to be the prototype of human autoimmune diseases. It is a disorder of generalized autoimmunity characterized by multisystem organ involvement, polyclonal B cell activation, and the production of autoantibodies against nuclear, cytoplasmic, and cell surface antigens. Autoreactive B and T lymphocytes can be found in healthy individuals as well, but their numbers are tightly regulated by a process of programmed cell death (apoptosis), which is crucial in the establishment of self-tolerance. Tolerance to self antigens can fail and can result in autoimmunity if there is a defect in the process of elimination of these cells.
SLE, as well as most other autoimmune diseases is difficult to diagnose. A strict definition of SLE patients included 4 or more of the 11 ACR revised criteria for SLE, eliminating LE cells but adding anticardiolipin antibodies and lupus anticoagulant as criteria (Tan, et al. Arthritis Rheum. 1982:25:1271-7). Often, a patient that is going to develop SLE will be kept off of treatment because they only show two or three of the criteria. One of the major tests, the ANA test (anti-nuclear antibodies), tests for the presence of these antibodies. However, 15-20% of those individuals with a positive ANA will never develop disease. The inadequacy of definitive tests for the diagnosis of autoimmune diseases is a recurrent theme. For this reason, treatment is often not started until disease is too far along and irreversible damage has occurred. Therefore development of a test for the diagnosis and susceptibility to autoimmune diseases could have a profound effect on the outcome of the disease and the patient's quality of life.
Several lines of evidence suggest that dysfunctional programmed cell death (apoptosis) might be involved in the pathogenesis of SLE and other autoimmune diseases. It has been postulated that in SLE, dysfunction of apoptosis could result in the inappropriate longevity of autoreactive B lymphocytes, allowing autoantibody levels to reach pathogenic thresholds and breakdown of self tolerance. Defective apoptosis of autoreactive lymphocytes is an attractive mechanism contributing to SLE, primarily because defects in either the apoptosis-promoting Fas gene or its ligand Fas-L (CD95L) accelerates autoimmunity in mouse strains (MRL-lpr/lpr and C3H-gld/gld, respectively) that exhibit SLE-like diseases. Furthermore, studies reveal links between autoimmunity and several other gene products involved in apoptosis. The bcl-2 gene enhances lymphocyte survival by inhibiting or delaying apoptosis. Transgenic mice overexpressing bcl-2 in their B cells show polyclonal B cell expansion and extended survival in vitro. After a few months, these mice developed an autoimmune syndrome resembling SLE.
Interleukin-10 (IL-10) is a pleiotropic cytokine that regulates many immune and inflammatory responses. Among other activities, this cytokine increases the survival of activated lymphocytes. Furthermore, administration of recombinant IL-10 to lupusprone (New Zealand black.times.New Zealand white)F.sub.1 ([NZB.times.NZW]F.sub.1) mice accelerates the development of autoimmunity. CTLA-4 is an additional gene involved in apoptosis that has been suggested to be associated with autoimmune disease development. CTLA4 can mediate antigen-specific apoptosis and appears to be part of a distinct signaling pathway capable of clonally deleting previously activated human T lymphocytes. CTLA-4 also warrants further study because it may be a candidate gene in more than one autoimmune disease. CTLA-4 was reported to be associated with 2 autoimmune diseases, Grave's disease and insulin-dependent diabetes mellitus.
In a recent publication, Eskdale et al (Tissue Antigens 1997:49:635-9) have shown an association between an IL-10 microsatellite polymorphism and SLE in a Caucasian population. In this study a group of 56 Caucasian SLE patients from Great Britain were compared with 102 ethnically matched controls. However, because of the moderate sample size, the results were considered only as a framework for further study.